CN113024454B - Synthesis method of brigatinib intermediate - Google Patents
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- CN113024454B CN113024454B CN202110318369.7A CN202110318369A CN113024454B CN 113024454 B CN113024454 B CN 113024454B CN 202110318369 A CN202110318369 A CN 202110318369A CN 113024454 B CN113024454 B CN 113024454B
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
The invention discloses a synthesis method of a brigatinib intermediate, wherein the brigatinib intermediate is 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidine-1-yl) aniline (I),the synthesis method comprises the steps of taking 5-fluoro-2-nitrobenzyl ether (II) and piperidone hydrochloride (III) as raw materials, carrying out substitution reaction to obtain a compound (IV), and carrying out catalytic reaction on the compound (IV) and N-methylpiperazine (V) in a hydrogen atmosphere to obtain an intermediate 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidin-1-yl) aniline (I).
Description
Technical Field
The invention relates to the field of pharmaceutical and chemical intermediate synthesis, in particular to a novel method for preparing a brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidin-1-yl) aniline by using 5-fluoro-2-nitrobenzyl ether and piperidone hydrochloride as starting raw materials.
Background
The Brigatinib is an antitumor drug developed by wutian corporation, is a new generation Tyrosine Kinase (TK) inhibitor, has obvious curative effect on ALK positive metastatic non-small cell lung cancer, is approved by FDA to be on the market in 4 months of 2017, has a sales volume of 8000 ten thousand yuan in 2018, and is expected to reach 4.78 billion in 2021. Brigatinib has the following advantages: (1) the inhibition effect of brigatinib on ALK positive is 12 times higher than that of brigatinib, and the brigatinib has high resistance to ALK mutants, so that the brigatinib can be used for treating patients with advanced disease or intolerant ALK positive metastatic non-small cell lung cancer after brigatinib treatment. (2) Clinical trial results indicate that brigatinib is currently the only anticancer drug that can extend PFS (progression free survival) in crizotinib-resistant patients by more than one year (13.9 months). (3) The effect of using brigatinib was also prominent in patients with brain metastases of ALK, with an objective intracranial remission rate of 67% and a disease control rate of 86%. Therefore, the future market prospect is huge, and the research on the synthesis method of the key intermediate 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidine-1-yl) aniline has theoretical research value and obvious economic benefit.
The structural formula of the 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine-1-yl) aniline (I) is shown as follows:
before the present invention was made, the main synthesis of 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (I) was as follows:
in 2004, WO 2004080980 discloses a method for preparing 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline, which comprises the steps of preparing 1- (3-methoxy-4-nitrophenyl) piperidin-4-one at 70-80 ℃ by using 5-fluoro-2-nitrobenzyl ether and piperidone hydrochloride as raw materials, carrying out reductive amination by equivalent sodium triacetyl borohydride, and finally carrying out hydrogenation by palladium-carbon at room temperature under the pressure of 0.5Mpa to reduce nitro groups to obtain a target product. The disadvantage is that the overall route yield is not high, 34.5%. The reducing agent sodium triacetyl borohydride is expensive and cannot be recycled. The synthetic route is as follows:
in 2016, a patent WO 2017076355A1 reports a preparation method of 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline, 5-fluoro-2-nitrobenzyl ether and 1-methyl-4- (piperidin-4-yl) piperazine are used as raw materials to prepare 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine at 70-80 ℃, and then a zinc powder/ammonium chloride system is used for reducing nitro groups to prepare a product, wherein the total yield is 68%. The disadvantages are that the price of the raw material 1- (1-methyl-4 piperidyl) piperazine is high, and zinc powder generates a large amount of danger, is not environment-friendly and is not beneficial to industrial production. The synthetic route is as follows:
in 2017, Zhang in patent WO2017088784 uses 5-fluoro-2-nitrobenzyl ether and piperidone hydrochloride as raw materials to generate 1- (3-methoxy-4-nitrophenyl) piperidine-4-ketone at 70-70 ℃, then 1- (3-methoxy-4-nitrophenyl) piperidine-4-ketone is subjected to reductive amination through a Leuckart-Wallach reaction (formic acid), and finally hydrogen is introduced at normal temperature by utilizing palladium-carbon at the pressure of 0.5MPa to reduce nitro groups into amino groups to generate target products. The synthetic route is as follows:
disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to provide a novel method for synthesizing 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline, which has the advantages of simple operation, low cost and mild reaction conditions and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a synthesis method of a brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (I) is characterized by comprising the following steps:
1) taking 5-fluoro-2-nitrobenzyl ether shown in a formula (II) and piperidone hydrochloride shown in a formula (III) as raw materials, adding a catalyst A, an organic solvent A and an alkali A, and stirring and reacting for 5-40 h at 50-100 ℃; after the reaction is finished, carrying out post-treatment on the reaction solution to obtain a compound (IV);
2) dissolving the compound (IV) and the compound (V) obtained in the step 1) in an organic solvent B, adding a dehydrating agent, reacting for 4-12h at 25-35 ℃, introducing hydrogen under the catalysis of a catalyst B, stirring and reacting for 10-40 h at room temperature-80 ℃ under the pressure of 0.3-1.5 MPa, and finally separating and purifying to obtain the target product 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidin-1-yl) aniline shown in the formula (I);
the synthesis method of the brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline is characterized in that in the step 1), the base A is at least one of triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, sodium hydroxide, potassium bicarbonate, 1, 8-diazabicycloundecen-7-ene and N, N-diisopropylethylamine, and preferably is potassium carbonate; the reaction temperature in the step 1) is 75-80 ℃.
The synthesis method of the brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidine-1-yl) aniline is characterized in that in the step 1), the organic solvent A is selected from one or more of the following: tetrahydrofuran, N-dimethylformamide, dichloromethane, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, water, a dimethyl sulfoxide-water mixed solvent, and an N, N-dimethylformamide-water mixed solvent; the organic solvent A is preferably a dimethyl sulfoxide-water mixed solvent with a volume ratio of 1: 0.5-2 or an N, N-dimethylformamide-water mixed solvent with a volume ratio of 1: 0.5-2, and the volume usage amount of the organic solvent A is 3-15 mL/g, preferably 5-8 mL/g, based on the mass of the 5-fluoro-2-nitrobenzyl ether shown in the formula (II).
The synthesis method of the brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidine-1-yl) aniline is characterized in that in the step 1), the catalyst A is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium iodide and ammonium iodide, and preferably tetrabutylammonium bromide; the amount of the substance of the catalyst A is 5 to 50%, preferably 10 to 20% of the amount of the substance of the compound (II). In the step 1), the ratio of the 5-fluoro-2-nitrobenzyl ether shown in the formula (II), the piperidone hydrochloride shown in the formula (III) and the alkali A is 1: 0.8-1.5: 1-3, preferably 1: 1.1-1.3: 2.0-2.2.
The synthesis method of the brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidine-1-yl) aniline is characterized in that in the step 1), the post-treatment process of the reaction liquid is as follows: and (3) cooling the reaction liquid to room temperature after the reaction is finished, pouring ice water into the reaction liquid to separate out a large amount of yellow solid, filtering, washing a filter cake with water to obtain a crude product, pulping the crude product with n-hexane, and finally drying to obtain the bright yellow solid compound (IV).
The synthesis method of the brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline is characterized in that in the step 2), the catalyst B is selected from a Pd/C catalyst or Raney Ni, the load of Pd in the Pd/C catalyst is 5-15%, and the catalyst B is preferably a Pd/C catalyst with the load of Pd of 10%; the mass amount of the catalyst B is 0.5-10%, preferably 3-5% of the mass of the compound (IV).
The synthesis method of the brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline is characterized in that in the step 2), the organic solvent B is selected from one or more of the following solvents: toluene, ethanol, methanol, acetonitrile, tetrahydrofuran; the organic solvent B is preferably tetrahydrofuran; the volume dosage of the organic solvent B is 4-15 mL/g, preferably 6-10mL/g based on the mass of the compound (IV).
The synthesis method of the brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidine-1-yl) aniline is characterized in that in the step 2), hydrogen is introduced into the step 2) to react under the pressure of 0.6-1.0 Mpa at the temperature of 50-55 ℃.
The synthesis method of the brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidin-1-yl) aniline is characterized in that in the step 2), the dehydrating agent is at least one of molecular sieve 4A, anhydrous sodium sulfate and anhydrous magnesium sulfate, and is preferably molecular sieve 4A; the mass ratio of the dehydrating agent to the compound (IV) is 1-3: 1; the mass ratio of the compound (IV) to the compound (V) is 1: 1.0 to 2.0, preferably 1: 1.4 to 1.5.
The synthesis method of the brigatinib intermediate 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidin-1-yl) aniline is characterized in that in the step 2), the steps of separation and purification are as follows: after the dehydrating agent and the catalyst B are removed by filtering the reaction solution, carrying out reduced pressure concentration on the filtrate to recover the solvent, and recrystallizing the obtained crude product by using a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 40-60: 1 to obtain the target product 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidin-1-yl) aniline shown in the formula (I).
When the dehydrating agent is molecular sieve 4A, the separation and purification steps in the step 2) are as follows: and (3) filtering the reaction liquid by using a titanium alloy net to recover a 4A molecular sieve (the 4A molecular sieve can be recycled after being calcined for 5 hours at 400 ℃ in a muffle furnace), further filtering the catalyst B, separating the reaction liquid from the catalyst B, directly washing a filter cake for 3-5 times by using a solvent, and supplementing a certain amount of fresh Pd/C, so that the reaction liquid can be used for the next batch of reaction. The same batch of catalyst can be used 3 times without affecting the yield. And (3) concentrating the filtrate under reduced pressure to recover the solvent, and recrystallizing the obtained crude product with a petroleum ether-ethyl acetate mixed solvent (the volume ratio is 40-60: 1) to obtain the compound (I).
Compared with the prior art, the invention has the advantages that:
1. the reaction process has short operation steps and is easy to operate;
2. no equivalent reducing agent is used;
3. the total yield and purity of the reaction are high, and the purity can reach 99.8 percent (HPLC area normalization method);
4. the catalyst B can be recycled, and the total cost is lower.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
The first embodiment is as follows: preparation of 1- (3-methoxy-4-nitrophenyl) piperidin-4-one (IV):
taking 500mL of four-neck flask provided with a stirring paddle, a thermometer and a condensing tube, adding 5-fluoro-2-nitrobenzyl ether (200mmol, 34.2g) and N, N-dimethylformamide (100mL), stirring for dissolving, sequentially adding potassium carbonate (500mmol,69g) and tetrabutylammonium bromide (20mmol,6.4g), heating to 75-80 ℃, adding piperidone hydrochloride (240mmol,36.7g) and water (100mL), reacting for 20 hours, finishing the reaction, cooling the reaction liquid to room temperature, pouring ice water (150mL), precipitating a large amount of yellow solid, filtering, washing a filter cake with water to obtain a crude product, pulping the crude product with N-hexane (150mL), putting into a vacuum drying oven, and drying to obtain a bright yellow solid target product compound (IV) 45g, wherein the yield is 90%, the purity is 98%, and the melting point is 168-plus 171 ℃.
In example one, the reaction solvent is DMF (100mL)/H 2 O(100mL)。
Pattern characterization of compound (iv):
1 H NMR(400MHz,CDCl 3 )δ＝8.02(d,J＝9.4Hz,1H),6.44(dd,J＝9.4,2.6Hz,1H),6.34(d,J＝2.6Hz,1H),3.97(s,3H),3.81(t,J＝6.2Hz,4H),2.65(t,J＝6.2Hz,4H). 13 C NMR(100MHz,CDCl 3 )δ206.5,156.4,153.9,129.6,129.1,104.7,96.4,56.2,45.6,39.9.HRMS(ESI):m/z calcd for C 12 H 14 N 2 O 4 [M+H] + 251.1026,found 251.1023。
example two: preparation of 2-methoxy-4- [4- (4-methyl-1-piperazinyl) -1-piperazinyl ] -aniline hydrochloride (I)
1- (3-methoxy-4-nitrophenyl) piperidin-4-one (40mmol,10g), N-methylpiperazine (60mmol,6g), CH were sequentially added to a 250mL autoclave 3 COOH (2mmol,0.12g), a 4A molecular sieve 20g and anhydrous tetrahydrofuran (70mL) are stirred for 8h at 30 ℃, a 10% Pd supported Pd/C catalyst (0.5g) is added, nitrogen is replaced for 3 times, hydrogen is injected, the pressure is 0.6-0.7 MPa, the temperature is raised to 50-55 ℃, the mixture is kept and stirred for 20h, the molecular sieve and the catalyst are respectively filtered and separated according to a recovery method, an organic phase is subjected to reduced pressure concentration, and n-hexane: recrystallization from ethyl acetate 50:1 gave 9.4g of a white solid. Yield 78% and purity 99.8% (mobile phase acetonitrile: 0.05% TFA/H) 2 O40: 60). Melting point 295-.
In example two, the reaction solvent was 70mL of anhydrous Tetrahydrofuran (THF); the dehydrating agent is 20g of 4A molecular sieve.
Pattern characterization of compound (i):
1 H NMR(400MHz,CDCl 3 )δ＝6.63(d,J＝8.4Hz,1H),6.52(d,J＝2.4Hz,1H),6.41(dd,J＝8.4,2.5Hz,1H),3.83(s,3H),3.56-3.49(m,3H),2.69-2.40(m,10H),1.92(dt,J＝12.8,3.0Hz,2H),1.71(qd,J＝12.2,3.9Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ147.9,145.3,129.9,115.4,109.7,102.8,61.7,55.4,55.4,51.5,48.9,46.0,28.3.HRMS(ESI):m/z calcd for C 17 H 28 N 4 O[M+H] + 305.2336,found305.2332。
example three to example fifteen:
preparation of 1- (3-methoxy-4-nitrophenyl) piperidin-4-one (IV), preparation method of each example the first example was repeated except that certain reaction conditions (such as type of reaction solvent, type of base A, charging molar ratio of 5-fluoro-2-nitrobenzyl ether (II) to piperidone hydrochloride (III), TBAB charging amount, etc.) were changed, and the reaction conditions and corresponding reaction effects specifically changed for each example are shown in tables 1-2.
TABLE 1
TABLE 2
In Table 1, examples three, four and five, the reaction conditions were changed to the types of reaction solvents, and the reaction solvents were replaced with 200mL of DMF, 200mL of DMSO and 200mL of MeCN, respectively. Examples six and seven, the reaction conditions varied were both the type of base a, which was replaced with 500mmol of sodium carbonate and 500mmol of potassium fluoride, respectively. The reaction conditions varied in example eight were the charge of piperidone hydrochloride (III) and in example eight the charge of piperidone hydrochloride (III) was 160mmol, so that the molar ratio of the charge of 5-fluoro-2-nitrobenzyl ether (II) to piperidone hydrochloride (III) in example eight was 1: 0.8.
in Table 2, the reaction conditions changed in example nine were the charge amount of piperidone hydrochloride (III), and the charge amount of piperidone hydrochloride (III) in example nine was 300 mmol. The reaction conditions changed in example ten and example eleven were reaction temperatures. Example twelve and example thirteen varied the reaction conditions were the charge of the catalyst tetrabutylammonium bromide (TBAB), which was 10mmol and 40mmol, respectively. The reaction conditions of the fourteen and fifteen changes are the reaction temperature and the charging amount of tetrabutylammonium bromide (TBAB) serving as a catalyst, and the charging amount of the TBAB in the fourteen and fifteen examples is 10mmol and 40mmol respectively.
Examples sixteen to twenty-eight:
preparation of 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (I), preparation method of each example repeat the second example except that certain reaction conditions are changed, and the specific changed reaction conditions and corresponding reaction effects of each example are shown in tables 3-4.
TABLE 3
TABLE 4
a: the dehydrating agent was replaced with anhydrous sodium sulfate (20 g).
In Table 3, the 10% specification Pd/C and the 5% specification Pd/C represent Pd/C catalysts having 10% Pd loading and 5% Pd loading, respectively. The reaction conditions changed in example twenty were the type of reaction solvent, which was replaced with 70mL of toluene. The reaction conditions changed in example twenty-one were the type of reaction solvent, which was replaced with 70mL of EtOH.
In Table 4, the reaction conditions changed in twenty-four and twenty-five examples are the charge amounts of N-methylpiperazine (V), which were 40mmol and 80mmol, respectively. The reaction conditions changed in example twenty-eight were the type of dehydrating agent, which was replaced with 20g of anhydrous sodium sulfate.
The description is given for the sole purpose of illustrating the invention concept in its implementation form and the scope of the invention should not be considered as being limited to the particular form set forth in the examples.
Claims (4)
1. The synthesis method of the brigatinib intermediate is characterized in that the brigatinib intermediate is 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (I), and the synthesis method comprises the following steps:
1) taking 5-fluoro-2-nitrobenzyl ether shown in a formula (II) and piperidone hydrochloride shown in a formula (III) as raw materials, adding a catalyst A, an organic solvent A and an alkali A, and stirring and reacting for 5-40 h at 50-100 ℃; after the reaction is finished, carrying out post-treatment on the reaction solution to obtain a compound (IV);
2) dissolving the compound (IV) and the compound (V) obtained in the step 1) in an organic solvent B, adding a dehydrating agent, reacting at 25-35 ℃ for 4-12h, introducing hydrogen under the catalysis of a catalyst B, stirring at room temperature-80 ℃ under the pressure of 0.3-1.5 MPa for reacting for 10-40 h, and finally separating and purifying to obtain a target product 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidin-1-yl) aniline shown in the formula (I);
in the step 1), the alkali A is potassium carbonate; the reaction temperature in the step 1) is 75-80 ℃;
in the step 1), the organic solvent A is selected from an N, N-dimethylformamide-water mixed solvent with the volume ratio of 1: 0.5-2, and the volume consumption of the organic solvent A is 5-8 mL/g based on the mass of the 5-fluoro-2-nitrobenzyl ether shown in the formula (II);
in the step 1), the catalyst A is selected from tetrabutylammonium bromide; the amount of the substance of the catalyst A is 10-20% of that of the compound (II); in the step 1), the mass ratio of the 5-fluoro-2-nitrobenzyl ether shown in the formula (II), the piperidone hydrochloride shown in the formula (III) and the alkali A is 1: 1.1-1.5: 2.0-2.2;
in the step 2), the catalyst B is selected from Pd/C catalysts with the load of 10 percent of Pd; the mass usage of the catalyst B is 3-5% of the mass of the compound (IV);
in the step 2), the organic solvent B is tetrahydrofuran; the volume dosage of the organic solvent B is 6-10mL/g based on the mass of the compound (IV);
in the step 2), introducing hydrogen to react under the pressure of 0.6-0.7 Mpa at the temperature of 50-55 ℃;
in the step 2), the dehydrating agent is at least one of a molecular sieve 4A, anhydrous sodium sulfate and anhydrous magnesium sulfate, and the mass ratio of the dehydrating agent to the compound (IV) is 1-3: 1; the mass ratio of the compound (IV) to the compound (V) is 1: 1.5 to 2.0.
2. The synthesis method of the intermediate of brigatinib as claimed in claim 1, wherein the dehydrating agent is molecular sieve 4A.
3. The synthesis method of the brigatinib intermediate as claimed in claim 1, wherein in the step 1), the reaction solution is post-treated by the following steps: and (3) cooling the reaction liquid to room temperature after the reaction is finished, pouring ice water into the reaction liquid to separate out yellow solid, filtering, washing a filter cake with water to obtain a crude product, pulping the crude product with n-hexane, and finally drying to obtain a bright yellow solid compound (IV).
4. The synthesis method of the brigatinib intermediate as claimed in claim 1, wherein in the step 2), the steps of separation and purification are as follows: after the dehydrating agent and the catalyst B are removed by filtering the reaction solution, concentrating the filtrate under reduced pressure to recover the solvent, and recrystallizing the obtained crude product with a petroleum ether-ethyl acetate mixed solvent at a volume ratio of 40-60: 1 to obtain the target product 2-methoxy-4- (4- (4-methylpiperazine-1-yl) piperidin-1-yl) aniline shown in the formula (I).
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